纯合型家族性高胆固醇血症诊疗进展

温文慧, 匡泽民, 吴月, 王旭, 武文峰, 王绿娅

温文慧, 匡泽民, 吴月, 王旭, 武文峰, 王绿娅. 纯合型家族性高胆固醇血症诊疗进展[J]. 协和医学杂志, 2019, 10(4): 387-392. DOI: 10.3969/j.issn.1674-9081.2019.04.015
引用本文: 温文慧, 匡泽民, 吴月, 王旭, 武文峰, 王绿娅. 纯合型家族性高胆固醇血症诊疗进展[J]. 协和医学杂志, 2019, 10(4): 387-392. DOI: 10.3969/j.issn.1674-9081.2019.04.015
Wen-hui WEN, Ze-min KUANG, Yue WU, Xu WANG, Wen-feng WU, Lü-ya WANG. Progress in the Diagnosis and Treatment of Homozygous Familial Hypercholesterolemia[J]. Medical Journal of Peking Union Medical College Hospital, 2019, 10(4): 387-392. DOI: 10.3969/j.issn.1674-9081.2019.04.015
Citation: Wen-hui WEN, Ze-min KUANG, Yue WU, Xu WANG, Wen-feng WU, Lü-ya WANG. Progress in the Diagnosis and Treatment of Homozygous Familial Hypercholesterolemia[J]. Medical Journal of Peking Union Medical College Hospital, 2019, 10(4): 387-392. DOI: 10.3969/j.issn.1674-9081.2019.04.015

纯合型家族性高胆固醇血症诊疗进展

详细信息
    通讯作者:

    王绿娅电话:010-64456436,E-mail:wangluya@126.com

  • 中图分类号: R596;R-1

Progress in the Diagnosis and Treatment of Homozygous Familial Hypercholesterolemia

More Information
    Corresponding author:

    Lü-ya WANG: WANG Lü-ya Tel: 86-10-64456436, E-mail: wangluya@126.com

  • 摘要: 家族性高胆固醇血症(familial hypercholesterolemia,FH)是严重遗传代谢性疾病,临床上分为纯合和杂合两种类型,纯合型FH(homozygous FH,HoFH)发病率为1/(16万~100万),被认为是罕见病。HoFH主要特点为极高水平的低密度脂蛋白胆固醇、多部位黄色瘤及早发动脉粥样硬化性心血管疾病,如不及时诊断、早期治疗, 青少年期即可发生心肌梗死甚至死亡。近年来,国际上也越来越重视FH的早期诊断和治疗,发布了多项FH指南与共识,我国亦结合国情制定了适合中国人的筛查诊断标准,为更好治疗FH提供了基础。本文就HoFH现有的诊断标准、鉴别诊断筛查和治疗方法进行综述,旨在提高医生对该病的认识。
    Abstract: Familial hypercholesterolemia (FH) is a serious hereditary metabolic disease. It is clinically divided into homozygous and heterozygous.The incidence of homozygous FH(HoFH) is 1/(160 000-1 000 000) and considered as a rare disease. HoFH is characterized by very high levels of low density lipoprotein cholesterol, multi-sited yellow tumors, and atherosclerosis cardiovascular disease. Without prompt diagnosis and early treatment, myocardial infarction and even death can occur in adolescence. In recent years, the international community has paid more and more attention to the early diagnosis and treatment of FH, and issued a number of guidelines and consensus on FH. China has also developed a screening and diagnostic standard suitable for Chinese people in combination with national conditions, which provides bases for better treatment of FH. This article reviewed HoFH's existing diagnostic criteria, differential diagnostic screening, and treatment methods, to improve physicians' understanding of the disease.
  • 在阿尔茨海默病(Alzheimer's disease,AD)临床诊断中,人们越来越多地发现患者的结构影像未显示海马萎缩,且海马萎缩可见于额颞叶痴呆。笔者曾观察过有认知功能进行性减退临床可能AD患者的影像学资料,结果病初及随访MRI均无海马萎缩,但有顶叶低代谢和萎缩。众所周知,淀粉样蛋白沉积形成的老年斑多数分布在新皮层,高度磷酸化的TUA蛋白沉积形成的神经原纤维缠结也不仅存在于内侧颞叶[1-2]。为此,笔者建立了系列研究:有病理基础的不同类型内侧颞叶萎缩与认知功能变化的相关性,不同脑叶与AD疾病进展的相关性,本文报告AD患者的顶叶变化。

    按照美国国立神经病及语言交流障碍和卒中研究所-阿尔茨海默病及相关疾病学会(National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association,NINCDSADRDA)诊断标准,选取2007年1月至2010年12月北京协和医院神经科门诊拟诊变性病性痴呆患者123例,经过详细的临床病史、疾病过程询问及神经系统检查后进行规范的梯度递进认知功能评价。

    选用简易精神状态量表(mini-mental state examination,MMSE)、蒙特利尔认知评估量表(Montreal cognitive assessment,MoCA)进行认知功能筛查,日常生活能力量表(activities of daily living,ADL)评价生活适应能力,医院焦虑抑郁量表(hospital anxiety and depression scale,HADS)评价情绪,再应用北京协和医院认知功能评价系统进行综合认知功能评价; 若患者有某项突出的认知功能障碍再进行专项评价,如汉语失语症、视空间功能评价等[3]。同时进行详细的鉴别诊断,除血常规、肝肾功能外特别注意感染如梅毒,代谢异常如甲状腺功能低下或亢进,营养障碍如维生素缺乏,中毒如酒精中毒、有机溶剂中毒、一氧化碳中毒等,还特别注意除外副肿瘤综合征等。将应用同样诊断程序临床诊断额颞叶痴呆作为不同类型痴呆的对照。

    脱氧葡萄糖正电子发射体层摄影术(fluorodeoxy glucose-positron emission tomography,FDG-PET)检测由专人完成,然后由2位以上观察者进行低代谢区评价,并测SUV值,设桥脑基底部SUV值为全脑SUV值的参照。再由专门的操作者单盲(不知道患者诊断)进行专项分析(NeuroQ)。在分析脑区时将通常观察中归为后部颞顶的区域进一步细分为顶叶和剪除顶叶后的单纯后部颞顶区。

    检查GRE T1和T2-FLARE基于体素的形态(voxel-based morphometric,VBM)、扩散张量成像(diffusion tensor imaging,DTI)和静息态功能,由专人分析结果,VBM同年龄组正常对照由核磁共振室提供。MRI显示顶叶萎缩通过轴位和矢状位图像确定。

    123例拟诊变性病性痴呆患者经检测41例符合可能AD,43例符合有可能AD。

    FDG-PET显示,84例(100%)可能AD和有可能AD患者均出现顶叶低代谢,67例(79. 8%)后扣带回低代谢,60例(71. 4%)后颞顶低代谢,52例(61. 9%)内侧颞叶低代谢。2例动态随访患者顶叶低代谢先于后扣带回(图 1),且患者随着随访期延长逐渐出现外部颞叶继而内部颞叶低代谢(图 2)。

    图  1  1例可能阿尔茨海默病患者FDG-PET随诊变化
    上图:顶叶/左侧外侧颞叶低代谢(红色); 下图: 1年后后扣带回及右侧外侧颞叶低代谢(红色)
    图  2  可能阿尔茨海默病患者FDG-PET随诊变化
    A.双侧外侧颞叶低代谢,右侧内侧颞叶部分低代谢(粉红色); B. 2年后右内侧颞叶低代谢加重,左内侧开始出现低代谢(粉红色)

    MRI显示矢状位自中线向两侧分别有超过4个层面萎缩,轴位自顶向下顶叶2个层面以上萎缩,内侧顶叶萎缩更重要。84例可能AD和有可能AD患者MRI图像显示,顶叶萎缩为67. 9% (57例双侧) ~ 84. 5% (71例单侧) (图 3); 而内侧颞叶萎缩(常规观察的萎缩)仅为26. 2% (22例双侧) ~ 35. 7% (30例单侧)。24例可用VBM分析患者的MRI显示顶叶萎缩明显重于对照组(图 4),且至少不轻于内侧颞叶萎缩。临床可能的12例额颞叶痴呆起病初期既没有顶叶萎缩也没有顶叶低代谢。额叶和外侧颞叶,后部颞顶区及内侧颞叶低代谢可见于AD和额颞叶痴呆。

    图  3  MRI示阿尔茨海默病患者顶叶萎缩
    A.轴位; B.矢状位
    图  4  基于体素的形态MRI示阿尔茨海默病患者较正常对照者顶叶皮层萎缩显著(黄色)

    在AD临床诊断和病理诊断中,海马及内侧颞叶变化具有重要的价值,且已得到广泛应用。代谢影像在10年前就证实了顶叶和后扣带回等部位代谢改变对AD诊断的重要价值。病理研究亦早已显示AD相关的变化不仅仅在内侧颞叶,β淀粉样蛋白沉积形成的老年斑多数分布在新皮层。随着临床研究手段的进展,在AD诊断中不同脑区的作用会越来越多地被认识到。本研究结果显示可能和有可能AD患者顶叶糖代谢减低出现率最高,且是最早出现的低代谢脑区之一,同时有明确的顶叶和/或内侧颞叶萎缩; 而额颞叶痴呆患者既没有突出的顶叶低代谢,也没有顶叶及内侧颞叶萎缩,提示顶叶影像学变化是AD的重要变化之一,可用于痴呆的鉴别诊断。笔者这一观点于2011年3月在加拿大召开的AD国际会议上通过大会发言报告。2011年5月AD协会发表的AD新诊断标准,除了指出MRI颞叶萎缩对AD的诊断价值外,也阐明了顶叶萎缩对提高诊断级别的价值[2, 4-6]

    2011年Womack等[7]曾提出内侧颞叶不是AD患者脑代谢异常的起源,并认为由后扣带回首发而后扩散至内侧颞叶。本研究也显示顶叶和后部颞顶区及外侧颞叶低代谢均早于内侧颞叶,只是本研究结果显示顶叶更早于后扣带回。本组患者均显示内侧颞叶低代谢发生率低于顶叶、额叶、外侧颞叶、后扣带回,动态随访患者也证实低代谢由顶叶/后扣带回/后部颞顶叶/外侧颞叶向内侧颞叶发展的过程。越来越多的研究证实了其低代谢的迟发性。

    以往研究在分析不同脑区的糖代谢时,将顶叶与颞叶划为颞顶一个区域分析,敏感性为93. 6%,本研究在应用NeuroQ分析时,将颞顶分为顶叶与后部颞顶区,顶叶在AD患者的低代谢发生率近100%,顶叶低代谢在AD更敏感且与其更相关。

    MRI示顶叶萎缩偶可见于非痴呆患者,但笔者目前有限地应用MRI VBM与同龄正常人进行组间对照的皮层结构评价资料(24例)证实,可能AD患者具有更突出的顶叶萎缩。2011年有关老年随访研究报道,顶叶萎缩患者部分发展为AD痴呆[8]。为此,本研究尚需进行以下两方面的扩展研究:更多的AD及其他类型变性病性痴呆患者的VBM研究; 有顶叶萎缩但尚无痴呆患者的长期随访研究。

    利益冲突  无
  • 表  1   HoFH主要临床诊断标准

    诊断标准 内容
    美国心脏学会2015年关于FH议程的科学声明[8] 满足以下3个条件之一:
        (1)LDL-C≥10 mmol/L且父母中至少一方为FH
        (2)LDL-C≥10 mmol/L且小于20岁患者有皮肤/肌腱黄色瘤或主动脉瓣疾病
        (3)如无家族史,患者LDL-C > 14 mmol/L (基因检测阳性时,LDL-C可 < 10 mmol/L)
    2014年欧洲动脉粥样硬化学会意见书:改善HoFH的检测与管理[9] 同时满足以下2个条件:
        (1)治疗前LDL-C ≥13 mmol/L或治疗后LDL-C≥ 8 mmol/L
        (2)10岁前出现皮肤/肌腱黄色瘤
    若父母均为HeFH,儿童或成人患者治疗后血脂水平类似父母血脂水平不能排除HoFH诊断
    2014年英国关于HoFH的管理声明[10] 满足以下3个条件之一:
        (1)儿童LDL-C > 11 mmol/L且10岁前出现皮肤/肌腱黄色瘤
        (2)成人LDL-C > 13 mmol/L且有皮肤/肌腱黄色瘤
        (3)血脂达到临床诊断标准且父母双方基因诊断均为HoFH
    2012日本动脉粥样硬化协会FH管理指南[11] 同时满足以下3个条件:
        (1)父母为HeFH
        (2)儿童期有早发ASCVD,特别是早发冠心病
        (3)TC≥16 mmol/L并伴有皮肤/肌腱黄色瘤
    中国《临床冠心病学》[12] 同时满足以下2个条件:
        (1)成人血清TC > 7.8 mmol/L或LDL-C > 4.4 mmol/L,16岁以下儿童TC > 6.7 mmol/L
        (2)患者或亲属有肌腱黄色瘤
    FH:家族性高胆固醇血症;HoFH:纯合型家族性高胆固醇血症;HeFH:杂合型家族性高胆固醇血症;LDL-C:低密度脂蛋白胆固醇;TC:总胆固醇;ASCVD:动脉粥样硬化性心血管疾病
    下载: 导出CSV
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  • 收稿日期:  2018-10-28
  • 刊出日期:  2019-07-29

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